Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19

Theobald, Sebastian J.; Simonis, Alexander; Georgomanolis, Theodoros; Kreer, Christoph; Zehner, Matthias; Eisfeld, Hannah S.; Albert, Marie‐Christine; Chhen, Jason; Motameny, Susanne; Erger, Florian; Fischer, Julia; Malin, Jakob J; Gräb, Jessica; Winter, Sandra; Pouikli, Andromachi; David, Friederike S.; Böll, Boris; Köehler, Philipp; Vanshylla, Kanika; Gruell, Henning; Suárez, Isabelle; Hallek, Michael; Fätkenheuer, Gerd; Jung, Norma; Cornely, Oliver A.; Lehmann, Clara; Tessarz, Peter; Altmüller, Janine; Nürnberg, Peter; Kashkar, Hamid; Klein, Florian; Koch, Manuel; Rybniker, Jan

doi:10.15252/emmm.202114150

Cited by 105 publications

(109 citation statements)

References 62 publications

(79 reference statements)

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“…The interplay between ACE2 and SARS-CoV-2 also triggers the NLRP3 inflammasome [ 23 ]. The SARS-CoV-2 S protein was recently shown to prime inflammasome formation and drive NLRP3 inflammasome activation in macrophages derived from patients with COVID-19 [ 8 ]. The SARS-CoV-2 S1 protein increases the NLRP3 level and caspase-1 activity in human PBMCs [ 9 ].…”

Section: Inflammasome Complex and Sars-cov-2 Infection In Covid-19 Patientsmentioning

confidence: 99%

“…Higher IL-1β levels are observed in the plasma of severely ill patients with COVID-19 [ 28 ]. The SARS-CoV-2 S protein promotes NLRP3 inflammasome activation and IL-1β secretion in COVID-19 patient-derived macrophages, and stimulation of the S protein upregulates both IL-1β and TNF-α; however, TNF-α is secreted in an NLRP3 inflammasome-independent manner [ 8 ]. In RNA sequencing, the SARS-CoV-2 S protein is observed to upregulate innate immunity-associated genes and several signalling pathways, including pro-inflammatory pathways, the NOD-like receptor, and the inflammasome signalling pathway.…”

Section: Inflammasome Complex and Sars-cov-2 Infection In Covid-19 Patientsmentioning

confidence: 99%

“…In RNA sequencing, the SARS-CoV-2 S protein is observed to upregulate innate immunity-associated genes and several signalling pathways, including pro-inflammatory pathways, the NOD-like receptor, and the inflammasome signalling pathway. In particular, the S protein increases TLR2 in CD14 + macrophages, and the S protein is correlated with a high level of TLR2 in cells derived from patients with COVID-19 [ 8 ]. In a single-cell RNA sequencing analysis, the upregulation of caspase expression in immune cells is observed in blood from patients with COVID-19.…”

Section: Inflammasome Complex and Sars-cov-2 Infection In Covid-19 Patientsmentioning

confidence: 99%

“…S protein-induced inflammasome activation is reversed by treatment with MCC950, and the release of IL-1β is also blocked in spite of S-protein exposure. Similarly, treatment with VX-765 (a caspase-1 inhibitor) suppresses NLRP inflammasome activation and the secretion of IL-1β [ 8 ]. Additionally, the development of nanovesicles through biomedical engineering may prevent the cytokine storm that occurs in patients with COVID-19 [ 60 ].…”

Section: Consideration Of Targeted Therapiesmentioning

confidence: 99%

“…There have been a growing number of studies on inflammasome activation induced by SARS-CoV-2 infection and COVID-19 severity in patients [ 2 , 7 ]. In particular, the SARS-CoV-2 S protein primes and drives the activation of the nucleotide-binding oligomerisation domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and the SARS-CoV-2 S1 protein triggers inflammasome activity alone [ 8 , 9 ]. The inflammasome is a macromolecular immune complex in cells, and it is involved in the extracellular release of IL-1β and IL-18 as well as in pyroptotic cell death [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory Response in COVID-19 Patients Resulting from the Interaction of the Inflammasome and SARS-CoV-2

Cheon

Koo

2021

IJMS

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The outbreak of the coronavirus disease 2019 (COVID-19) began at the end of 2019. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with COVID-19 may exhibit poor clinical outcomes. Some patients with severe COVID-19 experience cytokine release syndrome (CRS) or a cytokine storm—elevated levels of hyperactivated immune cells—and circulating pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. This severe inflammatory response can lead to organ damage/failure and even death. The inflammasome is an intracellular immune complex that is responsible for the secretion of IL-1β and IL-18 in various human diseases. Recently, there has been a growing number of studies revealing a link between the inflammasome and COVID-19. Therefore, this article summarizes the current literature regarding the inflammasome complex and COVID-19.

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Section: Inflammasome Complex and Sars-cov-2 Infection In Covid-19 Patientsmentioning

confidence: 99%

Section: Inflammasome Complex and Sars-cov-2 Infection In Covid-19 Patientsmentioning

confidence: 99%

Section: Inflammasome Complex and Sars-cov-2 Infection In Covid-19 Patientsmentioning

confidence: 99%

Section: Consideration Of Targeted Therapiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inflammatory Response in COVID-19 Patients Resulting from the Interaction of the Inflammasome and SARS-CoV-2

Cheon

Koo

2021

IJMS

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Association of Complement and MAPK Activation With SARS-CoV-2–Associated Myocardial Inflammation

et al. 2022

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IMPORTANCE Myocardial injury is a common feature of patients with SARS-CoV-2 infection. However, the cardiac inflammatory processes associated with SARS-CoV-2 infection are not completely understood.OBJECTIVE To investigate the inflammatory cardiac phenotype associated with SARS-CoV-2 infection compared with viral myocarditis, immune-mediated myocarditis, and noninflammatory cardiomyopathy by integrating histologic, transcriptomic, and proteomic profiling.DESIGN, SETTING, AND PARTICIPANTS This case series was a cooperative study between the Ludwig Maximilian University Hospital Munich and the Cardiopathology Referral Center at the University of Tübingen in Germany. A cohort of 19 patients with suspected myocarditis was examined; of those, 5 patients were hospitalized with SARS-CoV-2 infection between March and May 2020. Cardiac tissue specimens from those 5 patients were compared with specimens from 5 patients with immune-mediated myocarditis, 4 patients with non-SARS-CoV-2 viral myocarditis, and 5 patients with noninflammatory cardiomyopathy, collected from January to August 2019. EXPOSURES Endomyocardial biopsy. MAIN OUTCOMES AND MEASURESThe inflammatory cardiac phenotypes were measured by immunohistologic analysis, RNA exome capture sequencing, and mass spectrometry-based proteomic analysis of endomyocardial biopsy specimens. RESULTS Among 19 participants, the median age was 58 years (range, 37-76 years), and 15 individuals (79%) were male. Data on race and ethnicity were not collected. The abundance of CD163+ macrophages was generally higher in the cardiac tissue of patients with myocarditis, whereas lymphocyte counts were lower in the tissue of patients with SARS-CoV-2 infection vs patients with non-SARS-CoV-2 virus-associated and immune-mediated myocarditis. Among those with SARS-CoV-2 infection, components of the complement cascade, including C1q subunits (transcriptomic analysis: 2.5-fold to 3.6-fold increase; proteomic analysis: 2.0-fold to 3.4-fold increase) and serine/cysteine proteinase inhibitor clade G member 1 (transcriptomic analysis: 1.7-fold increase; proteomic analysis: 2.6-fold increase), belonged to the most commonly upregulated transcripts and differentially abundant proteins. In cardiac macrophages, the abundance of C1q was highest in SARS-CoV-2 infection. Assessment of important signaling cascades identified an upregulation of the serine/threonine mitogen-activated protein kinase pathways.CONCLUSIONS AND RELEVANCE This case series found that the cardiac immune signature varied in inflammatory conditions with different etiologic characteristics. Future studies are needed to examine the role of these immune pathways in myocardial inflammation.

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Mitochondrial regulation of acute extrafollicular B‐cell responses to COVID‐19 severity

Cao

Liu

et al. 2022

Clinical & Translational Med

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Background Patients with COVID‐19 display a broad spectrum of manifestations from asymptomatic to life‐threatening disease with dysregulated immune responses. Mechanisms underlying the detrimental immune responses and disease severity remain elusive. Methods We investigated a total of 137 APs infected with SARS‐CoV‐2. Patients were divided into mild and severe patient groups based on their requirement of oxygen supplementation. All blood samples from APs were collected within three weeks after symptom onset. Freshly isolated PBMCs were investigated for B cell subsets, their homing potential, activation state, mitochondrial functionality and proliferative response. Plasma samples were tested for cytokine concentration, and titer of Nabs, RBD‐, S1‐, SSA/Ro‐ and dsDNA‐specific IgG. Results While critically ill patients displayed predominantly extrafollicular B cell activation with elevated inflammation, mild patients counteracted the disease through the timely induction of mitochondrial dysfunction in B cells within the first week post symptom onset. Rapidly increased mitochondrial dysfunction, which was caused by infection‐induced excessive intracellular calcium accumulation, suppressed excessive extrafollicular responses, leading to increased neutralizing potency index and decreased inflammatory cytokine production. Patients who received prior COVID‐19 vaccines before infection displayed significantly decreased extrafollicular B cell responses and mild disease. Conclusion Our results reveal an immune mechanism that controls SARS‐CoV‐2‐induced detrimental B cell responses and COVID‐19 severity, which may have implications for viral pathogenesis, therapeutic interventions and vaccine development.

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Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19

Cited by 105 publications

References 62 publications

Inflammatory Response in COVID-19 Patients Resulting from the Interaction of the Inflammasome and SARS-CoV-2

Inflammatory Response in COVID-19 Patients Resulting from the Interaction of the Inflammasome and SARS-CoV-2

Association of Complement and MAPK Activation With SARS-CoV-2–Associated Myocardial Inflammation

Mitochondrial regulation of acute extrafollicular B‐cell responses to COVID‐19 severity

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